The proper development and maintenance of a multicellular organism is a complex process that requires precise spatial and temporal control of cell proliferation. Cell proliferation is controlled via an intricate network of extracellular and intracellular signaling pathways that process growth regulatory signals. This signaling network is superimposed upon the basic cell cycle regulatory machinery that controls particular cell cycle transitions. In eukaryotes, the cell cycle is comprised of an ordered series of discrete events. In contrast to the periodicity of eukaryotic DNA replication and mitosis, cellular growth requires that most metabolic reactions occur continuously. The cell cycle regulatory machinery coordinates the events that occur during the cell cycle, as well as cell growth. Protein degradation is an important aspect of the development and maintenance of multicellular organisms, as it provides direction, order, and the appropriate timing for the key events that occur during the cell cycle.
The problem of how cell division is controlled has long been a topic of intense research. Early models suggested the existence of an initiator that would accumulate during the cell cycle, and induce DNA replication or mitosis when it reached a critical concentration. The mitotic process would then inactivate the initiator, thereby "resetting" the cell cycle. Subsequent research showed that mitotic cyclins accumulate during interphase to drive entry of cells into mitosis. These cyclins are then degraded at the end of mitosis, in order to reset the cycle. Protein degradation has been shown to have a pervasive role in the regulation of cell cycle progression. For example, proteolysis is required for multiple mitotic processes, and for initiating DNA replication (See, King et al., Science 274:1652-1659 [1996]). Nonetheless, much remains unknown regarding the proteins and the interactions that are involved in the proteolytic regulation of the cell cycle and other processes. Indeed, many proteins are likely to be involved in proteolysis and cellular maintenance (as well as other processes). Such information is needed for the development of compounds to regulate the cell cycle and prevent or treat diseases associated with abnormal cell proliferation.